The long term goal of these studies is to understand the role of oxygen gradients in cardiac morphogenesis, and as a corollary how disruptions in oxygen supply or utilization in critical developmental windows may cause heart defects. Embryonic tissues of warm-blooded animals develop under reduced and varying oxygen tensions reflecting the maturation and efficiency of the gas- exchangers, oxygen carrying capacity of the blood, admixture of oxygenated and de-oxygenated blood, and organ-specific vasculogenesis (oxygen delivery). We have proposed that superimposed on this generalized hypoxia are tissue oxygen gradients that have specific morphogenetic roles in the heart. We observed that the OFT myocardium is hypoxic relative to other chamber myocardium during a period of dynamic remodeling of the cardiac OFT in the transition to a dual series circulation. The maturation of the cardiac OFT requires elimination of cells by PCD, recruitment and patterning of endothelial progenitor cells in coronary vasculogenesis, recruitment of cells from the neural crest required for OFT septation and innervation, and PCD-dependent remodeling of the OFT cushion mesenchyme to form the valves and septae. Ambient hypoxia/hyperoxia or the forced expression of Hypoxia-Inducible factor (HIF-1a) is not sufficient to activate PCD in the embryonic heart, consistent with other models, but does cause defects in OFT structure and neural and vascular patterning. This leads to the hypothesis that tissue oxygen gradients condition the myocardium to respond to death or growth signals and patterns the heart through the recruitment and organization of extra-cardiac cell populations.
Aim 1 will test the role of Endothelial Progenitor Cell invasion in triggering PCD of the hypoxic OFT myocardium in avian models through physical or gene-mediated ablation of this cell population.
Aim 2 will define the program of gene expression that is under the control of hypoxia/HIF-1 in the embryonic heart and OFT in vivo.
Aim 3 will use conditional inactivation of HIF-1a in specific cell populations in the mouse heart to test its role in OFT remodeling and patterning, and test for gene-environment interactions through hypobaric hypoxic exposures in developing mice in which HIF-1 is inactivated. Significance: Clinical and epidemiological studies suggest that reduced oxygen delivery to the fetus and oxidative stress may cause congenital heart defects. If oxygen gradients play a role in specific morphogenic processes, as proposed here, then these processes should be particularly susceptible to disruptions of oxygen delivery and metabolism. Conotruncal and outlet heart defects are common in the human population but for most the etiology is unknown.
Clinical, epidemiological and basic studies suggest that reduced oxygen delivery, as occurs with utero-placental insufficiency or at high altitudes, or interference with oxidative metabolism and oxidative stress may cause congenital heart defects (67;71;83) (24;144). If oxygen gradients and relative lack of oxygen play a role in specific morphogenic processes, as proposed here, then these processes should be particularly susceptible to disruptions of oxygen delivery and metabolism. Conotrouncal heart defects are common in the human population but for most the etiology is unknown.
|Kenchegowda, Doreswamy; Liu, Hongbin; Thompson, Keyata et al. (2014) Vulnerability of the developing heart to oxygen deprivation as a cause of congenital heart defects. J Am Heart Assoc 3:e000841|
|Outeda, Patricia; Huso, David L; Fisher, Steven A et al. (2014) Polycystin signaling is required for directed endothelial cell migration and lymphatic development. Cell Rep 7:634-44|
|Yang, Peixin; Kenchegowda, Doreswamy; Fisher, Steven A (2014) Cardiac myocyte proliferation: not as simple as counting sheep. J Mol Cell Cardiol 74:125-6|
|Wikenheiser, Jamie; Karunamuni, Ganga; Sloter, Eddie et al. (2013) Altering HIF-1* through 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure affects coronary vessel development. Cardiovasc Toxicol 13:161-7|
|Karunamuni, Ganga; Yang, Ke; Doughman, Yong Qiu et al. (2010) Expression of lymphatic markers during avian and mouse cardiogenesis. Anat Rec (Hoboken) 293:259-70|
|Vickerman, Mary B; Keith, Patricia A; McKay, Terri L et al. (2009) VESGEN 2D: automated, user-interactive software for quantification and mapping of angiogenic and lymphangiogenic trees and networks. Anat Rec (Hoboken) 292:320-32|
|Wikenheiser, Jamie; Wolfram, Julie A; Gargesha, Madhusudhana et al. (2009) Altered hypoxia-inducible factor-1 alpha expression levels correlate with coronary vessel anomalies. Dev Dyn 238:2688-700|
|Yang, Ke; Doughman, Yong-Qiu; Karunamuni, Ganga et al. (2009) Expression of active Notch1 in avian coronary development. Dev Dyn 238:162-70|
|Liu, Hongbin; Yang, Qiwei; Radhakrishnan, Krishnan et al. (2009) Role of VEGF and tissue hypoxia in patterning of neural and vascular cells recruited to the embryonic heart. Dev Dyn 238:2760-9|
|Liu, Hongbin; Fisher, Steven A (2008) Hypoxia-inducible transcription factor-1alpha triggers an autocrine survival pathway during embryonic cardiac outflow tract remodeling. Circ Res 102:1331-9|
Showing the most recent 10 out of 22 publications